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An efficient synthesis for [(14) C]Omarigliptin (MK-3102) is described. The initial synthesis of a key (14) C-pyrazole moiety did not work due to the lack of stability of (14) C-DMF-DMA reagent. Thus, a new radiolabeled synthon, (14) C-biphenylmethylformate, was synthesized from (14) C-sodium formate in one step in 92% yield and successfully used in construction of the key (14) C-pyrazole moiety. Regioselective N-sulfonation of the pyrazole moiety was achieved through a dehydration-sulfonation-isomerization sequence. [(14) C]MK 3102 was synthesized in five steps from (14) C-biphenylmethylformate with 25% overall yield.

The synthesis of stable isotope labeled (SIL) complex drug molecules with a ≥3 mass unit increase from the parent compound is essential for drug discovery and development. Typical approaches that rely on H, C, and N isotopes can be very challenging or even intractable, and can delay the drug development process. This work introduces a new concept for the synthesis of labeled compounds that relies on the use of S. The synthetic utility of S was demonstrated with the efficient synthesis of [ S]phosphorothioates [ S ]-PS-ODNs-TTT and [ C, N, S]-ceftolozane. In addition, a procedure for the direct oxidation of phosphites to [ S]phosphorothioates using elemental S without isotope dilution was developed.

The specific activities for a series of S‐35 tracers were found to vary from the decay‐corrected specific activity of the labeled reagent. If not known before the stock solution preparation and binding assay, this variation would have resulted in performing the assay at approximately two to three times over the targeted concentration, thereby leading to considerable error in the calculated binding and related conclusions. Copyright © 2012 John Wiley & Sons, Ltd.

Tritium radiopharmaceuticals are often used in drug development because of their desirable specific activity. The inherent instability of these radioactive tracers often leads to a requirement to purify prior to use. Purification methodologies such as preparative chromatography and solid/liquid extractions often utilize water as a solvent, which is not suitable for long-term storage and necessitates removal. Rotary evaporation has traditionally been utilized for the removal of this unwanted solvent, however, this method has been shown to lead to decomposition of the tritium species in some cases. Centrifugal evaporation is a milder concentration method which has been demonstrated to effectively remove solvents. In this study, we show that centrifugal evaporation leads to effective concentration of tritium samples without the decomposition typically observed by rotary evaporation.

Radiolabeled compounds are essential tools in drug development used to obtain critical metabolism and safety information. To support the synthesis and ensure quality of radiolabeled compounds for all programs, bench automation has been implemented in our laboratories. The concept of a platform technology for bench-top automation is not new. A considerable investment in the automation of various critical analytical laboratory workflows to both harmonize the efforts of a large and diverse global organization and minimize capital footprint has been made on our part. Various custom automation techniques and applications have been developed to increase capabilities and productivity of radiochemical analyses at Merck. In this paper, we will present a novel system that is capable of automating the liquid scintillation counting procedure. The system has handled multiple radiolabeled ((3)H, (14)C, and (35)S) pharmaceutical compounds with an accuracy of 5% with a standard deviation of 2% and a cycle time of ~10 min per analysis.

Tritium tracers are frequently used in biological assays during the drug discovery process because of their high specific activity and relative ease of synthesis. However, this high specific activity, along with other contributing factors, can lead to an increased rate of radiolytic decomposition. As a result, following long-term storage tritium tracers often require purification. Understanding the elements that cause radiolytic decomposition is extremely important to extend the storage life, and consequently reduce unnecessary inventory purifications. One of these elements is the presence of water in tritium tracers. Upon investigation, it was discovered that aside from the relatively common tritium/water exchange that could occur, residual water could also contribute significantly to the decomposition of tritium tracers. A near-infrared method was developed utilizing a portable device to measure the water content in tritium tracers rapidly and without sample destruction. This method proved to be quick, efficient, and achieved an error less than 5% compared to that of traditional Karl Fischer titration. Method validation was performed and good accuracy, linearity, limit of detection and quantitation were all established.